Organic compounds -- part of the class 532-570 series – Organic compounds – Fatty compounds having an acid moiety which contains the...
Reexamination Certificate
2000-03-14
2001-08-14
Carr, Deborah D. (Department: 1621)
Organic compounds -- part of the class 532-570 series
Organic compounds
Fatty compounds having an acid moiety which contains the...
C514S558000, C514S560000
Reexamination Certificate
active
06274751
ABSTRACT:
This invention refers to wax esters enriched in &ohgr;-3 unsaturated fatty acids, to the procedure to obtain them, to their peculiar biochemical behaviour which enables them to be used as drug and food additives, and to formulations which contain them for both pharmaceutical and dietetic-alimentary purposes.
The name “wax” usually means a wide class of lipids, which are characterized more according to their physical feature than according to their chemical structure. Generally, a material is classified as a wax when it looks like honeycomb material.
On the contrary, from a strictly chemical point of view, waxes are particular carboxylic esters (wax esters). Namely, they are esters of long chain aliphatic acids (fatty acids) with long chain aliphatic alcohols. Both acids and alcohols can be either saturated or unsaturated. A full description of nature and characteristics of wax esters can be found in a review by P. E. Kolattukudy, “Chemistry and Biochemistry of Natural Waxes”, Elsevier (1976), Amsterdam.
The starting material to be used in the preparation of products herein described is a mixture of esters enriched in &ohgr;-3 unsaturated fatty acids. This mixture is usually obtained by current industrial procedures from natural sources such as fish oil, containing a relatively high amount of polyunsaturated &ohgr;-3 fatty acids, such as EPA (eicosapentaenoic acid) and DHA (docosahexaenoic acid). In a common procedure, fish oil triglycerides are split by treatment with low boiling alcohols in the presence of a catalyst. After removing glycerol, esters thus obtained are further enriched in &ohgr;-3 unsaturated fatty acids by some techniques, such as distillation and urea fractionation.
Methyl and ethyl esters, enriched in EPA and DHA, along with natural or synthetical triglycerides, and free fatty acids, also enriched in EPA and DHA, have been the forms so far available for material enriched in &ohgr;-3 polyunsaturated acid, to be used as both pharmaceuticals and food integrators.
These forms have severe drawbacks, mainly due to their tendency to oxidation. These products go easily rancid when exposed to air. Oxidation by-products, even at a low content, render the main material stenching, irritant and disgusting, so that this cannot be easily handled and utilized.
From a technological standpoint, moreover, polyunsaturated fatty acids, their glycerides, and their esters with low boiling alcohols are thick oily liquids, so they are hard to formulate. The best solution so far used is to formulate them in soft jelly capsules, but also this expedient is not able to cancel inconveniences such as burping after ingestion.
Surprisingly, we have found that wax esters herein described can easily override these difficulties. Products herein described are easily handled since they are solid and less prone to oxidation. Nevertheless, the biological properties remain the same as in the case of all those oily derivatives mentioned before. Surprisingly, as a matter of fact, we have discovered that wax esters enriched in &ohgr;-3 polyunsaturated fatty acids are much more readily absorbed and metabolized than wax esters naturally encountered, characterized by a low contents in &ohgr;-3 fatty acids.
Products herein described are solid waxy materials, so that oxidation is limited to the only surface layer. Therefore, they can be formulated in several ways, preserving their biological and organoleptic properties.
Beneficial effects of &ohgr;-3 fatty acids, particularly of EPA and DHA, are well known for pathologies affecting the cardio-circulatory system (thrombosis, atherosclerosis, platelet hyperaggregation, hyperlipidhemia, hypercholesterolhemia), as well as for pathologies affecting the immune system, in inflammatory states, and in tumors. Moreover, the effects of lack of dietary DHA have been described (Tacconi M. T., Lligona L., Salmona M., Pitsikas M., and Algeri S., Neurobiol. of Aging, 12:55-59, 1990).
This invention concerns therefore also the use of wax esters herein described in the preparation of drugs which can conveniently used in the aforementioned pathologies, as well as in the preparation of dietetic and alimentary formulations.
Wax esters herein described are prepared from a mixture of esters of free fatty acids enriched in polyunsaturated fatty acids, where the alcohol moiety is usually methyl or ethyl alcohol, or, more generally, a low boiling alcohol. This mixture is reacted with one or more alcohols via a transesterification reaction, provided that these alcohols are the same ones found in natural wax esters, according to the following scheme:
RCOOR″+R′OH=RCOOR′+R″OH
where
R: residue of an &ohgr;-3 unsaturated fatty acid,
R″: methyl, ethyl, or a low boiling alcohol residue,
R′:residue of an alcohol contained in natural wax esters.
For R, EPA and DHA residues are preferred. For R″, methyl and ethyl are preferred. Finally, for R′, residues of saturated alcohols are preferred, with a number of carbon atoms ranging from 12 and 40. Another preferred alcohol is oleyl alcohol.
The aforementioned scheme is not restrictive, since a mixture of esters RCOOR″ can be simultaneously reacted with a mixture of alcohols R′OH, provided that, as stated before, the mixture represented by the formula RCOOR″ is enriched in &ohgr;-3 unsaturated fatty acids, i.e., as an example, when RCOOR″ represents the esters of EPA and DHA, these are contained in this mixture in percentage higher than 18% and 12% respectively, corresponding to the percentages of these two acids usually found in natural products.
Optimally, the reaction is performed starting from nearly stoichiometric amount of the reactants, and it is catalyzed by bases, according to procedures usually adopted for transesterifications. The product is obtained with the highest yield when low boiling alcohol R″OH is removed as a reaction product by distillation under reduced pressure.
After completion, the reaction mixture is treated with hot water containing small amounts of an acid, preferably citric acid, in order to quench and remove the catalyst, along with small traces of soap formed during the reaction. Further addition of hot water separates the wax ester as a melted liquid phase, which is allowed to separate and to solidify.
Wax esters described by this invention can be recrystallized in small white needle-shaped crystals. They can also be purified without any crystallization, simply by repeating the washing of the oily phase with some more water and citric acid. The product thus obtained can undergo a final treatment of deodorization, in order to remove by-products from oxidation, according to procedures usually used in alimentary oil technology.
According to the procedure thus described, the content of &ohgr;-3 unsaturated fatty acids in the final wax ester is the same as in the starting mixture of esters, as shown by the analysis of the acidic moiety obtained by hydrolysis of wax esters.
Transesterification reaction is the best suited procedure in order to obtain wax esters highly enriched in polyunsaturated fatty acids, but also other reactions can give the same products, starting both from esters enriched in polyunsaturated acids and from free fatty acids obtained by hydrolizing these esters. Some of these reactions can be mentioned, such as direct esterification of free fatty acids with alcohols, treatment of alcohols with reactive derivatives of acids, such as anhydrides, chlorides, isopropenyl esters, and so on, interesterification of either methyl or ethyl esters of fatty acids with either acetic or propionic esters of long chain alcohols.
Wax esters herein described are more stable toward air oxidation than the starting esters, as shown by the parallel determination of peroxide number, made at increasing times, of a sample of ethyl ester enriched in EPA and DHA and of the corresponding wax ester, when both samples were allowed to stand in an open vessel. After one week of exposure to air, peroxide number was increased from five to sev
Carr Deborah D.
Nixon & Vanderhye
Prime European Therapeuticals S.p.A.
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